The compound 5-hydroxytryptamine (5-HT or 5HT), also known as serotonin or enteramine, is a known vasoactive agent and endogenous neurotransmitter acting on receptors both within and outside the central nervous system and on blood vessels. Drugs acting on these receptors are known as 5-HT agonists or antagonists. These 5-HT receptors have been further classified into several receptor sub-classes, some of which themselves contain sub-types, and are designated, for example, 5-HT1, 5-HT1-like, 5-HT1.sub.B, 5-HT1.sub.D, 5-HT2, 5-HT3, and so on.
5-HT1-like agonists and agonists at other 5-HT1 sites comprise a known subclass of therapeutics with a variety of uses, notably including migraine therapy. Representative members of this class of compounds include sumatriptan succinate (distributed under the name Imitrex.TM. by GlaxoWellcome). Sumatriptan and related 5-HT agonist heterocyclic compounds are described in U.S. Pat. No. 4,816,470 to Dowle et al., the teachings of which are incorporated by reference. Note is made of ergot alkaloids which have 5-HT receptor activity, and these drugs are distinct from sumatriptan and its analogs in their chemical structure. In addition, ergots exhibit additional pharmacological properties distinct from sumatriptan. Ergot alkaloids and related compounds such as dihydroergotamine mesylate (DHE 45) are identified with 5-HT agonist receptor activities and have been used in migraine therapy. Without being bound by any particular theory, it is believed that the efficacy of ergots in relieving migraine arises, in part, from pharmacological activity distinct from the recognized 5-HT1 agonist property. Particular reference is made to ergotamine tartrate, ergonovine maleate, and ergoloid mesylates (i.e. dihydroergocornine, dihydroergocristine, dihydroergocryptine (dihydro-.alpha.-ergocryptine and dihydro-.beta.-ergocryptine), and dihydroergotamine mesylate.
Some of these agents are not reliably effective treatments for migraine. However, some agents are useful in the treatment of migraine, but after an initial therapeutic effect in some patients, migraine symptoms are seen again within about 1-24 hours after the initial relief. That is, after a dosage of a therapeutic agent has been administered to a subject in an amount to effectively treat a migraine, and migraine palliation has been observed, migraine symptoms occur again from as soon as about 1-8 hours after first relief to about 12 to 24 hours later. It will be appreciated that individual migraineurs display individualized symptoms and timing for this phenomenon as will treatment with particular therapeutic agents.
In some forms of migraine, certain patients have found total or partial relief with the use of analgesics such as acetaminophen and phenacetin and other non-steroidal non-opiate analgesics not generally classified as anti-inflammatory. While, these agents, when taken alone, are rarely effective in providing complete and rapid relief of all the symptoms of migraine, especially when the symptoms of the attack already include nausea or vomiting, in combination therapy of the present invention their effectiveness is surprisingly increased.
As outlined by K. M. A. Welch (New Eng. J Med, 1993:329; 1476-1483), the initial dosages of the analgesics useful for the treatment of migraine are: aspirin, 500-650 mg; acetaminophen, 500 mg; naproxen sodium, 750-825 mg; tolfenamic acid, 200-400 mg; and, ibuprofen 200 mg. After oral dosing, peak plasma concentrations in subjects not experiencing a migraine attack usually occur at or about 1 hour for aspirin and acetaminophen, and between 1-2 hours for naproxen sodium, tolfenamic acid, and ibuprofen.
The headache, which occurs under the circumstances described above, has been variously and interchangeably termed a "rebound," "relapse," "recurrent," or "secondary" headache. The terms not withstanding, it is presently unknown as to whether this later headache is a continuation of the physiological chain of events that caused original headache, or a new headache due to other or repeated but unrelated underlying pathology. It is also possible that the follow on headache is a response to therapeutic agents which initially were successful in treating the initial migraine symptoms. The terms "rebound", "relapse," "recurrent" and "secondary" (as defined below) are considered synonymous as used herein without inferring a mechanism or cause of the headache described above.
It has been reported that of the 50 to 70% of patients who experience migraine symptom relief within 2 hours from initial dosing with a 5-HT agonist, 30-50% experience migraine symptoms again within the next 1-24 hours. In view of the extreme discomfort and long duration of pain that characterizes migraine headaches, a therapy that reduces or avoids rebound migraine is of substantial importance.
Note is made of certain studies illuminating aspects of migraine therapy and of observed recurrent headache after treatment with a 5-HT agonist, the teachings of which are incorporated by reference.
1. Sumatriptan-A reappraisal of its pharmacology and therapeutic efficacy in the acute treatment of migraine and cluster headache. Plosker G L et al.; Drugs 1994:47:622-655 PA1 2. Subcutaneous Sumatriptan in a clinical setting: The first 100 consecutive patients with acute migraine in a tertiary care center. Sheftell F D et al.; Headache 1994:34:67-72 PA1 3. Migraine and cluster headache--their management with sumatriptan: a critical review of the current clinical experience. Wilkinson M et al.; Cephalalgia 1995;15:337-357 PA1 4. Treatment of the migraine attack. Silberstein S D; Current Opinion in Neurology 1994;7:258-263 PA1 5. Drug therapy of migraine. Welch K M A; New Eng. J Med; 1993;329: 1476-1483 PA1 6. Recent advances in the acute management of migraine and cluster headaches. Kumar K L; J Gen Int Med 1994;9:339-348 PA1 A. "Long acting" in relation to NSAIDs shall mean a pharmacokinetic half-life of at least about 4-6 hours and preferably about 8-14 hours and a duration of action equal to or exceeding about 6-8 hours. Particular reference is made to flurbiprofen with a half-life of about 6 hours; ketoprofen with a half-life of about 2 to 4 hours; naproxen and naproxen sodium with half-lives of about 12 to 15 hours and about 12 to 13 hours respectively; oxaprozin with a half-life of about 42 to 50 hours; etodolac with a half-life of about 7 hours; indomethacin with a half-life of about 4 to 6 hours; ketorolac with a half-life of up to about 8-9 hours; nabumetone with a half-life of about 22 to 30 hours; mefenamic acid with a half-life of up to about 4 hours; and piroxicam with a half-life of about 4 to 6 hours. PA1 B. "Therapeutically effective amount" as to a drug dosage, shall mean that dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that migraine headache is not well understood and the etiologies of particular migraine attacks vary, as does the response to particular drugs. Thus reference to "specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment" is a recognition that a "therapeutically effective amount," administered to a particular subject in a particular instance will not abort migraine onset or relieve an actual migraine headache, even though such dosage is deemed a "therapeutically effective amount" by those skilled in the art. It is to be further understood that drug dosages are, in particular instances, measured as oral dosages, or parenteral or inhaled dosages or with reference to drug levels as measured in blood. PA1 C. "Co-timely" as to drug administration shall mean administration of a second drug for migraine relief while a first drug for migraine relief is present in a therapeutically effective amount. It is to be understood that in some instances this will require sequential administration. In some instances, multiple routes of administration will be employed such as intravenous or subcutaneous injection of an 5-HT agonist, while a long acting NSAID is taken orally from prior to or subsequent to such 5-HT agonist injection. PA1 D. "Coordinated" in the practice of the present invention combining 5-HT agonist and NSAID administration shall mean administration of an NSAID such that effective plasma levels of the NSAID will be present in a subject from about one hour to about 12-24 hours after the onset of migraine or onset of precursor symptoms of a migraine. In some embodiments this will be about 1 to 12 hours after a 5-HT agonist has been administered. The coordination time is clearly related to the route of NSAID administration. That is, for example, i.m. routes will generally have shorter lead times to peak plasma level than oral routes. With oral NSAID formulations, it is noted that the time to peak plasma levels for particular NSAIDs is as follows: flurbiprofen peaks in about 1 to 2 hours; ketoprofen peaks in about one-half to 2 hours; naproxen and naproxen sodium peak at about 2 to 4 hours and 1 to 2 hours respectively; oxaprozin peaks at about 3 to 5 hours; etodolac peaks at about 1 to 2 hours; indomethacin peaks at about 1 to 4 hours; ketorolac peaks at about one-half to 1 hour; nabumetone peaks at about 2.5 to 4 hours; mefenamic peaks at about 2 to 4 hours; meclofenamate peaks in 0.5-1 hours; and piroxicam peaks at about 3 to 5 hours. PA1 E. "5-HT agonist" is to be broadly understood to include 5-HT agonists of all types, including but not limited to 5-HT1-like agonists, 5-HT1B, and 5-HT 1D agonists. Particular reference is made to sumatriptan succinate and related 5-HT agonist heterocyclic compounds described in U.S. Pat. No. 4,816,470 to Dowle et al.; ergot alkaloids and related compounds such as dihydroergotamine mesylate (DHE 45), ergotamine tartrate, ergonovine maleate, ergoloid mesylates (i.e. dihydroergocornine, dihydroergocristine, dihydroergocryptine (dihydro-.alpha.-ergocryptine and dihydro-.beta.-ergocryptine); Pfizer CP-93129 as described in European Patent Application 379314 (the teachings of which are incorporated herein by reference), and Allelix ALX 1323; Merck L 741604; SmithklineBeecham SB 220453; and Almirall LAS31416, zolmitriptan GlaxoWellcome licensed to Zeneca; and naratriptan to GlaxoWellcome. In addition, other pharmacologically related compounds are contemplated as within the ambit of this invention. PA1 F. "Relapse headache" variously and interchangeably termed a "rebound, relapse, recurrent or secondary" headache shall mean headaches experienced most notably by that portion of the migraineur population that, while experiencing initial relief (or avoidance of migraine in the case of treated precursor symptoms) upon administration of a 5-HT agonist, experience return of migraine or migraine symptoms within the next about 1 to 24 hours. As noted above, this group comprises perhaps 40% of those subjects that experience returns of migraine or migraine symptoms, whom initially respond to 5-HT agonist therapy. Although it is presently unknown if this is a continuation of the original headache, a new headache either due to the ongoing underlying pathology or perhaps related to the administration of the therapeutic agents used initially to treat the migraine symptoms, these terms will be considered synonymous as used herein without inferring a mechanism or cause of the secondary headaches described above. PA1 G. "Initial migraine relief" shall be understood to be the reduction or abolition of migraine symptoms from first onset of either a migraine attack or the precursor indicia of a migraine headache such as the aura and visual "scotoma" in about a 24 hour period. PA1 H. "Unit dosage form" shall mean single drug administration entity. By way of example, a single tablet, capsule, dragee, or trochee, suppository, or syringe combining both an 5-HT agonist and an NSAID would be a unit dosage form. Administration of a unit dosage form will result in blood levels of the NSAID required to produce a therapeutic effect within about the first hour after dosing and will still be present at least about 8-12 hours after initial dosing, and in particular instances, for as long as about 24 hours after dosing. Blood levels of the 5-HT agonist normally associated with a therapeutic effect will be present within the first hour and should persist in measurable quantities for at least about 4-6 hours. In the particular example of the NSAID naproxen sodium about 550 mg combined with the 5-HT agonist sumatriptan of about 25 mg, results in blood levels of naproxen ion of approximately 40 mcg/ml within 1 hour after dosing and blood levels exceeding approximately 20 mcg/ml present about 12 hours after dosing and, in particular instances, as long as about 18-24 hours after dosing. Blood levels of sumatriptan will be approximately 10 ng/ml within the first hour after dosing and will remain in measurable quantities for at least about 4-6 hours. PA1 I. "Quick dissolve" in reference to a tablet or other oral dosage forms shall mean that the oral dosage form is at least about 95% dissolved within 20 minutes of administration. In determining "quick dissolve" reference is made to standard USP test methodology. PA1 J. "Enhanced therapeutic effect" in the context of this invention shall mean that the initial relief of migraine symptoms will occur more quickly with a claimed combination of two agents compared to the same doses of each component given alone; or that doses of one or both component(s) below what would otherwise be a (apparently) minimum effective dose (a "sub-MED").